In general, WS cells have a high level of genomic instability, with increased amounts of DNA deletions, insertions, and rearrangements. These effects could potentially be the result of defects in DNA repair, replication, and/or recombination, although the actual biochemical defect remains unknown. We are comparing WRN to the other RecQ helicases. There are five human RecQ proteins and all are involved in the maintenance of genome stability. We are especially interested in defining the unique and shared roles of WRN and the other RecQ helicases in double strand break repair. Confocal microscopy is used to investigate the dynamic behavior of WRN and its interacting partners. There are multiple pathways whereby a cell can repair a double strand break (DSB) and recently we investigated WRN's role in DSB repair pathway choice (Homologous Recombination (HR) vs classical Non-Homologous End Joining (c-NHEJ) vs Alternative NHEJ (alt-NHEJ)). We find that WRN regulates resection at the 5' ends of DSBs, and influences the choice between c-NHEJ and alt-NHEJ. In mouse cells lacking Wrn and Trf2, we found that alt-NHEJ is favored leading to an increased frequency of telomere fusions. Thus, alt-NHEJ may be driving genomic instability in WRN-deficient cells. The implications from this work are that small molecule inhibitors of alt-NHEJ may have therapeutic benefit in WRN-deficient cells by preventing genomic rearrangements and genome stability.